This invention relates to derivatives of penicillins and cephalosporins, and more particularly to sulfur analogs of 6-aminopenicillanic acid and 7-aminocephalosporinic acid and biologically active derivatives thereof.
In U.S. Pat. No. 3,159,617, there is taught the first commercial synthesis of 6.beta.-aminopenicillanic acid and penicillin derivatives based thereon. A vast number of derivatives of the 6.beta.-aminopenicillanic acid may be formed by introduction of various groups into the amino group of the acid. Thus, acyl groups, isocyanates, isothiocyanates, halogen compounds, methylisoureas, ethylene oxide, ethylene imine, and the like have been introduced into the amino group of the 6.beta.-aminopenicillanic acid to form both biologically active and biologically inactive derivatives.
Many of the derivatives of 6.beta.-aminopenicillanic acid, especially those derivatives formed by acylation, have become useful drugs. For example, ampicillin and carbenicillin have broadened the spectra of activity to include use against certain Gram-negative organisms while methicillin shows good activity against certain resistant staphylococci.
In an effort to find new biologically active derivatives of 6.beta.-aminopenicillanic acid, attempts have been made to modify the parent compounds by myriad methods, in addition to the mere functionalization of the amino group. Thus, stimulated by the elucidation of the structure of the cephalosporins, there have been attempted modifications of the thiazolidine moiety of 6.beta.-aminopenicillanic acid. This transformation is particularly useful since cephalosporins are not readily available from nature. Thus, much effort has been concentrated on the investigation of possible transformations of the thiazolidine ring to the dihydrothiazine ring without any concomitant change of the chemically sensitive .beta.-lactam moiety. These efforts are described by D. H. R. Barton and T. G. Sammes, Proc. R. Soc. Lond. B, 179 345 (1971).
Other attempts have been made to modify 6.beta.-aminopenicillanic acid through reaction of the .beta.-lactam moiety, but such attempts are relatively few and are focused on variation of the substituents of sterochemistry of the C-6 carbon in the penam system. Primarily, four types of modifying reactions are reported, namely acylation, epimerization, alkylation and diazotization.
One successful example of the epimerization reaction is reported by G. E. Gutowski, Tet.Lett., (1970), 1779 and 1863. However, this penicillin having the epimerized C-6 substituent is devoid of any biological activity. With regard to alkylation at the C-6 position, most attempts, based upon earlier predictions that the introduction of an .alpha.-methyl group at the C-6 position might enhance antibiotic activity, have been directed to such introduction. Further, both direct and indirect .alpha.-hydroxylalkylation of the penicillin nucleus at C-6 with benzaldehyde an formaldehyde has been reported by R. Riner and P. Zeller, Helv., Chim., Acta 51, 1905 (1968). These derivatives and other .alpha.-alkylated derivatives show some biological activity, but both display substantially less activity than the well known penicillin G.
Deamination of 6.beta.-aminopenicillanic acid by sodium nitrite in mineral acid proceeds with inversion at C-6, resulting in the C-5 and C-6 protons being trans-oriented in the product. Moreover, when the reaction is run in the presence of a haloacid, a 6.alpha.-halo product is obtained. Deamination of 6.beta.-aminopenicillanic acid by sodium nitrite with oxy acids is reported by T. Hauser and H. P. Sigg, Helv. Chim. Acta, 50, 1327 (1967). With such oxy acids, 6.alpha.hydroxypenicillanic acid is isolated as the benzyl ester. Ready transformation produces the .alpha.-oxygen analog, of penicillin V, 6 .alpha.-phenoxyacetoxypenicillanic acid. This material also exhibits no biological activity.
Similar chemical transformations and derivatizations in the cephalosporin antibiotic series are reported in part by R. B. Morin and B. G. Jackson, "Chemistry of Cephalosporin Antibiotics, " Progress in the Chemistry of Organic Natural Products XXVIII, Wein, Springer-Verlag (1970).
Further, two new series of these penicillins and cephalosporins have recently been described in copending U.S. patent applications Ser. Nos. 347,772, filed Apr. 3, 1973, 494,507, filed Aug. 5, 1974, and 616,979, filed Sept. 26, 1975. These series, the carbon and oxygen analogs of penicillins and cephalosporins, are characterized by the replacement of the 6.beta.-nitrogen of the "normal" antibiotic with carbon or oxygen respectively. These novel analogs and the wide variety of derivatives obtainable therefrom are biologically active and provide new series of antibiotics.
For brevity, the commonly accepted abbreviations of 6-APA for 6.beta.-aminopenicillin acid, 6-OPA and 6-CPA for the oxygen and carbon analogs thereof, 7-ACA for 7.beta.-aminocephalosporanic acid and 7-OCA and 7-CCA for the oxygen and carbon analogs thereof will be used throughout the specification.